Acetaminophen

Last Updated on Tue, 10 Jan 2023 | Drug Safety

Name: ACETAMINOPHEN
Class: Analgesic/Antipyretic
Risk Factor: B

Fetal Risk Summary

Acetaminophen is routinely used during all stages of pregnancy for pain relief and to lower elevated body temperature. The drug crosses the placenta (1). In therapeutic doses, it is apparently safe for short-term use. However, continuous, high daily dosage in one mother probably caused severe anemia (possibly hemolytic) in her, and fatal kidney disease in her newborn (2).
The pharmacokinetics of acetaminophen in pregnancy have been reported (3,4). In six healthy women who ingested a 1000-mg dose at 36 weeks' gestation and again 6 weeks after delivery, the mean serum half-lives were similar, 3.7 hours and 3.1 hours, respectively (3). The absorption, metabolism, and renal clearance of the drug were similar in the pregnant and nonpregnant states. A 1994 study compared the pharmacokinetics of a single 650-mg acetaminophen oral dose in ten nonpregnant women (controls) with eight women at a mean gestational age of 11.1 weeks (4). Among the pharmacokinetic parameters evaluated, significant differences between the pregnant vs. controls were found for elimination constant (0.431 vs. 0.348/Hr; p<0.01), serum half-life (1.62 vs. 2.02; p<0.005), and clearance (7.14 vs. 5.22 L/Hrkg; p=0.03).
The potential for acetaminophen-induced fetal liver toxicity after a toxic maternal dose was first suggested in 1979 (5). Two recent reports have described such toxicity (6,7). A woman, in her 27th–28th week of pregnancy, ingested 29.5 g of acetaminophen over less than 24 hours for severe dental pain (6). Fetal movements were last felt about 23 hours after the first dose, and on presentation to the hospital 16 hours later, no fetal heartbeat was heard. The mother eventually recovered, although her serum levels of acetaminophen by extrapolation were thought to exceed 300 µg/mL, a toxic level. Autopsy of the 2190-g female fetus revealed a liver acetaminophen concentration of 250 mg/g of tissue. The extensive lysis of the fetal liver and kidneys, which may have been caused by autolysis before delivery (approximately 3 days after the mother last felt fetal movement), prevented documentation of the characteristic lesions observed in acetaminophen overdose (6).
A 1997 report described the fatal outcomes of a 38-year-old woman and her fetus at 31 weeks' gestation after she consumed an acute 35-g acetaminophen dose (7). The woman presented to the hospital 26 hours after the overdose with signs and symptoms of hepatorenal failure. On admission, she had a toxic acetaminophen serum level (40.43 µg/mL) which was predictive of a very high risk of hepatocellular damage and subsequent fulminant liver failure (7). IV administration of N-acetylcysteine was started 30 minutes after admission. Severe fetal distress was diagnosed 30 minutes later and a cesarean section under spinal anesthesia was performed to deliver a 1620-g female infant who had Apgar scores of 0, 0, and 1 at 1, 5, and 10 minutes, respectively. The infantŠ½s acetaminophen serum level was 41.42 µg/mL. Despite intensive therapy, the infant died 34 hours after birth and the mother died 66 hours after the overdose. Although the infant's laboratory data indicated hepatorenal toxicity, the actual cause of death could not be determined as permission for autopsy was refused (7).
In four other cases of acute overdosage, acetaminophen-induced fetal liver toxicity was apparently not observed, although such damage may have resolved before delivery in some cases (8,9,10 and 11). One woman, at 36 weeks' gestation, consumed a single dose of 22.5 g of acetaminophen, producing toxic blood levels of 200 µg/mL (8). She was delivered of a normal infant approximately 6 weeks later. In another case, a woman at 20 weeks' gestation consumed a total of 25 g in two doses during a 10-hour period (9). She gave birth at 41 weeks to a normal infant with an occipital cephalohematoma as a result of birth position. At 24 hours of age, the infant had jaundice that responded to phototherapy. No evidence of permanent liver damage was observed. The jaundice was thought to have been caused by the cephalohematoma. A third case of acute maternal overdose occurred at 15.5 weeks of gestation when a mother ingested 64 g of the drug (10). Her acetaminophen level 10 hours after the ingestion was 198.5 µg/mL. Marked hepatic necrosis and adult respiratory distress syndrome (because of aspiration pneumonia) ensued and then gradually resolved. The patient was discharged home approximately 3 weeks after ingestion and subsequently was delivered of a healthy 2000-g male infant at 32 weeks' gestation. The infant had physiologic hyperbilirubinemia with a peak level on the 4th day of life of 10.3 mg/dL, but phototherapy was not required. Follow-up evaluation at 4 months indicated normal development. One case involved a 22-year-old woman in her 31st week of pregnancy who consumed a 15-g dose, followed by a 50-g dose 1 week later (11). Fetal distress was observed 16 hours after the second overdose, as evidenced by a complete lack of fetal movements and breathing, a marked decrease in fetal heart rate beat-to-beat variability with no accelerations, and a falling baseline rate. Because of the fetal condition, labor was induced (cesarean section was excluded because of the mother's incipient hepatic failure). Eighty-four hours after the overdose, a healthy 2198-g female infant was delivered with Apgar scores at 1 and 5 minutes of 9 and 10, respectively. Except for hypoglycemia, mild respiratory disease, and mild jaundice, the newborn did well. Liver enzymes were always within the normal range, and the jaundice was compatible with immaturity. Acetaminophen was not detected in the cord blood. Follow-up examinations of the infant at 6 weeks and again at 6 months were normal. In each of these instances, protection against serious or permanent liver damage was probably afforded by the prompt administration of intravenous N-acetylcysteine.
A 1993 report described a 25-year-old woman at 27 weeks' gestation who consumed 12.5–15 g of acetaminophen as a single dose 36 hours before admission for premature labor (12). She had also consumed an unknown amount of the drug over a few days before the acute overdose. Because of severe fetal distress, a cesarean section was performed under general anesthesia before her preoperative laboratory tests indicating liver failure were available. A 1300-g male infant was delivered who had Apgar scores of 1, 4, and 4 at 1, 5, and 10 minutes, respectively. No mention was made of hepatic or other toxicity in the infant and his course was thought to be satisfactory for his gestational age. The mother was treated for progressive liver failure and eventually recovered.
The Rocky Mountain Poison and Drug Center reported the results of a nationwide study on acetaminophen overdose during pregnancy involving 113 women (13). Of the 60 cases that had appropriate laboratory and pregnancy outcome data, 19 occurred during the 1st trimester, 22 during the 2nd trimester, and 19 during the 3rd trimester. In those cases with a potentially toxic serum level of acetaminophen, early treatment with N-acetylcysteine was statistically associated with an improved pregnancy outcome by lessening the incidence of spontaneous abortion and fetal death. Only one congenital anomaly was observed in the series, and that involved a 3rd trimester overdose with nontoxic maternal acetaminophen serum levels (13). Based on these observations, neither acetaminophen nor N-acetylcysteine were likely teratogens, although follow-up data on the infants were not available (13).
A Teratology Information Service in England conducted a prospective study of the pregnancy outcomes of 300 women who had consumed an overdose of acetaminophen, either alone, or as a combination product (14). The overdoses occurred in all trimesters: 118 (39.3%), 103 (34.3%), and 79 (26.3%) in the 1st, 2nd, and 3rd trimesters, respectively. Systemic antidote treatment consisted of N-acetylcysteine (N=33), ipecac (N=52), and methionine (N=16). In the remaining 199 cases, treatment was not recorded or not given, or a variety of nonsystemic treatments (charcoal, gastric lavage or miscellaneous) were used. The fetal outcomes included 219 (72%) normal infants (two sets of twins), 16 (5%) spontaneous abortions (10 within 3 weeks of the overdose), 2 (1%) late fetal deaths, 54 (18%) elective abortions (1 with a diaphragmatic hernia), and ll (4%) newborns with malformations (exposed between 16 and 32 weeks' gestation). All of the spontaneous abortions and one late fetal death occurred after 1st trimester overdoses. The other late fetal death followed a 2nd trimester overdose. The majority of the elective abortions were conducted for “social” rather than medical reasons. Malformations included one each of systolic murmur, small port wine stain on occiput, cleft lip and palate, bilateral inguinal hernia, soft palate defect, spina bifida occulta/bilateral squint, hypospadias, and ptosis of left eye. There were three cases of talipes. The malformation rate was within the expected rate in England and none of the cases, including the one case of diaphragmatic hernia, can be related to acetaminophen (14). Seven full-term newborns had neonatal complications (all exposed during the 2nd or 3rd trimesters). The complications do not appear to be related to acetaminophen overdose (14). Moreover, evaluations up to at least 6 weeks of age did not demonstrate any clinical signs of renal or hepatotoxicity.
The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 226 of whom had 1st trimester exposure to acetaminophen (15, pp. 286–295). Although no evidence was found to suggest a relationship to large categories of major or minor malformations, a possible association with congenital dislocation of the hip based on three cases was found (15, p. 471). The statistical significance of this association is unknown, and independent confirmation is required. For use anytime during pregnancy, 781 exposures were recorded (15, p. 434). As with the qualifications expressed for 1st trimester exposure, possible associations with congenital dislocation of the hip (eight cases) and clubfoot (six cases) were found (15, p. 484).
A 1982 report described craniofacial and digital anomalies in an infant exposed in utero to large daily doses of acetaminophen and propoxyphene throughout pregnancy (16). The infant also exhibited withdrawal symptoms as a result of the propoxyphene (see also Propoxyphene). The authors speculated with caution that the combination of propoxyphene with other drugs, such as acetaminophen, might have been teratogenic. In a study examining 6,509 women with live births, acetaminophen with or without codeine was used by 697 (11%) during the 1st trimester (17). No evidence of a relationship to malformations was observed.
In a surveillance study of Michigan Medicaid recipients conducted between 1985 and 1992 involving 229,101 completed pregnancies, 9,146 newborns had been exposed to acetaminophen during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 423 (4.6%) major birth defects were observed (416 expected). Specific data were available for six defect categories, including (observed/expected) 87/91 cardiovascular defects, 16/16 oral clefts, 4/7 spina bifida, 30/27 polydactyly, 14/16 limb reduction defects, and 16/22 hypospadias. These data do not support an association between the drug and the defects.
Using data from the North Jutland Pharmaco-Epidemiological Prescription Database in Denmark, investigators identified 123 women who had received a prescription for acetaminophen during pregnancy and/or 30 days before conception (18). The pregnancy outcomes of these women were compared with 13,329 controls who had received no prescriptions. Among the offspring of the 55 women who had received an acetaminophen prescription up to 30 days before conception and/or the 1st trimester, there were six (10.9%) infants with congenital malformations compared with 697 (5.2%) from controls. The odds ratio (OR) for malformations was 2.3 (95% confidence interval [CI] 1.0–5.4). The six malformations were ventricular septal defect, two congenital dislocations of the hip, stenosis of tear canal, diaphragmatic hernia, and megalocornea (keratoglobus). The nature of the defects do not indicate a causal relationship to acetaminophen (18). No increased risk of malformation was found when the analysis was restricted to primigravidas (OR 0.7, 95% CI 0.1–5.5) (18). In addition, no effect was observed on fetal growth.
Unlike aspirin, acetaminophen does not affect platelet function, and there is no increased risk of hemorrhage if the drug is given to the mother at term (19,20). In a study examining intracranial hemorrhage in premature infants, the incidence of bleeding after exposure of the fetus to acetaminophen close to birth was no different from that in nonexposed control infants (see also Aspirin) (21).
A 1993 study examined the effect of therapeutic levels of acetaminophen on prostacyclin (PGI2) production by endothelial cells isolated from human umbilical veins in culture and during the 3rd trimester in women with either hypertension or various complications of pregnancy (22). The drug reduced the production of PGI2 in culture and during pregnancy, but thromboxane (TxA2) production was not affected in the women. A balance between PGI2 and TxA2 is thought to be critical during pregnancy. PGI2, derived from endothelial cells, is vasodilatory and antiaggregatory, compared with the platelet-derived TxA2, which is vasoconstrictive and proaggregatory (22). PGI2 production increases normally during pregnancy, but this increase is markedly inhibited in pregnancy-induced hypertension (PIH) (22). Thus, a significant acetaminophen-induced reduction in PGI2 production could adversely affect pregnancies complicated by PIH, including those treated with low-dose aspirin (see Aspirin). Because the effects of acetaminophen on PGI2 are known to be tissue-specific, the authors of this study cautioned that additional studies, such as those measuring the effect of acetaminophen on placental PGI2 and in patients being treated with low-dose aspirin for PIH, are required before the clinical significance of their findings can be determined (22).
In a prospective study of 1,529 pregnant women studied in the mid-1970s, acetaminophen was used in the first half of pregnancy by 41% (23). Using a computerized system for stratifying on maternal alcohol and smoking histories, 421 newborns were selected for follow-up. Of this group, 43.5% had been exposed in utero to acetaminophen in the first half of pregnancy. After statistical control of numerous potentially confounding covariates, the data indicated that acetaminophen was not significantly related to child IQ at 4 years of age or to attention variables (see Aspirin for opposite results). Three physical growth parameters (height, weight, and head circumference) were also not significantly related to in utero acetaminophen exposure.
Acetaminophen has been used as an antipyretic just before delivery in women with fever secondary to chorioamnionitis (24). A significant improvement in fetal and newborn status, as measured by fetal heart rate tracings and arterial blood gases, was observed after normalization of the mother's temperature.

Breast Feeding Summary

Acetaminophen is excreted into breast milk in low concentrations (25,26,27,28 and 29). A single case of maculopapular rash on a breast-feeding infant's upper trunk and face was described in 1985 (25). The mother had taken 1 g of the drug at bedtime for 2 days before the onset of the symptoms. The rash resolved 24 hours after discontinuing acetaminophen. Two weeks later, the mother took another 1-g dose, and the rash recurred in the infant after breast feeding at 3, 8, and 12 hours after the dose. Milk levels at 2.25 and 3.25 hours after the dose were 5.78/7.10 µg/mL (right/left breasts) and 3.80/5.95 µg/mL (right/left breasts), respectively. These represented milk:plasma ratios of 0.76 and 0.50, respectively.
Unpublished data obtained from one manufacturer showed that after an oral dose of 650 mg, an average milk level of 11 µg/mL occurred (personal communication, McNeil Laboratories, 1979). Timing of the samples was not provided.
In 12 nursing mothers (nursing 2-22 months) given a single oral dose of 650 mg, peak levels of acetaminophen occurred at 1-2 hours in the range of 10–15 µg/mL (26). Assuming 90 mL of milk were ingested at 3-, 6-, and 9-hour intervals after ingestion, the amount of drug available to the infant was estimated to range from 0.04% to 0.23% of the maternal dose. After ingestion of a single analgesic combination tablet containing 324 mg of phenacetin, average milk levels of acetaminophen, the active metabolite, were 0.89 µg/mL (27). Milk:plasma ratios at 1 and 12 hours were 0.91 and 1.42, with a milk half-life of 4.7 hours, as compared with 3.0 hours in the serum. Repeated doses at 4-hour intervals were expected to result in a steady-state concentration of 2.69 µg/mL. In three lactating women, a mean milk:plasma ratio of 0.76 was reported after a single oral dose of 500 mg of acetaminophen (28). In this case, the mean serum and milk half-lives were 2.7 and 2.6 hours, respectively. Peak milk concentrations of 4.2 µg/mL occurred at 2 hours. In a more recent study, the calculated milk:plasma ratio was approximately 1.0 (29). Based on a dose of 1000 mg, the estimated maximum dose the infant could ingest was 1.85% of the maternal dose. Except for the single case of rash, no other adverse effects of acetaminophen ingestion via breast milk have been reported. The American Academy of Pediatrics considers acetaminophen to be compatible with breast feeding (30).

References

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